Structural and functional interactions between the EF hand domain and S2-S3 loop in the type-1 ryanodine receptor ion channel.

Previous cryo-electron micrographs suggested that the skeletal muscle Ca2+ release channel, ryanodine receptor (RyR)1, is regulated by intricate interactions between the EF hand Ca2+ binding domain and the cytosolic loop (S2-S3 loop). However, the precise molecular details of these interactions and functional consequences of the interactions remain elusive. Here, we used molecular dynamics simulations to explore the specific amino acid pairs involved in hydrogen bond interactions within the EF hand-S2-S3 loop interface. Our simulations unveiled two key interactions: (1) K4101 (EF hand) with D4730 (S2-S3 loop) and (2) E4075, Q4078, and D4079 (EF hand) with R4736 (S2-S3 loop). To probe the functional significance of these interactions, we constructed mutant RyR1 complementary DNAs and expressed them in HEK293 cells for [3H]ryanodine binding assays. Our results demonstrated that mutations in the EF hand, specifically K4101E and K4101M, resulted in reduced affinities for Ca2+/Mg2+-dependent inhibitions. Interestingly, the K4101E mutation increased the affinity for Ca2+-dependent activation. Conversely, mutations in the S2-S3 loop, D4730K and D4730N, did not significantly change the affinities for Ca2+/Mg2+-dependent inhibitions. Our previous finding that skeletal disease-associated RyR1 mutations, R4736Q and R4736W, impaired Ca2+-dependent inhibition, is consistent with the current results. In silico mutagenesis analysis aligned with our functional data, indicating altered hydrogen bonding patterns upon mutations. Taken together, our findings emphasize the critical role of the EF hand-S2-S3 loop interaction in Ca2+/Mg2+-dependent inhibition of RyR1 and provide insights into potential therapeutic strategies targeting this domain interaction for the treatment of skeletal myopathies.

Inhibition of Estradiol Signaling in the Basolateral Amygdala Impairs Extinction Memory Recall for Heroin-Conditioned Cues in a Sex-Specific Manner.

INTRODUCTION: Relapse is a major treatment barrier for opioid use disorder. Environmental cues become associated with the rewarding effects of opioids and can precipitate relapse, even after numerous unreinforced cue presentations, due to deficits in extinction memory recall (EMR). Estradiol (E2) modulates EMR of fear-related cues, but it is unknown whether E2 impacts EMR of reward cues and what brain region(s) are responsible for E2s effects. Here, we hypothesize that inhibition of E2 signaling in the basolateral amygdala (BLA) will impair EMR of a heroin-associated cue in both male and female rats. METHODS: We pharmacologically manipulated E2 signaling to characterize the role of E2 in the BLA on heroin-cue EMR. Following heroin self-administration, during which a light/tone cue was co-presented with each heroin infusion, rats underwent cued extinction to extinguish the conditioned association between the light/tone and heroin. During extinction, E2 signaling in the BLA was blocked by an aromatase inhibitor or specific estrogen receptor (ER) antagonists. The next day, subjects underwent a cued test to assess heroin-cue EMR. RESULTS: In both experiments, females took more heroin than males (mg/kg) and had higher operant responding during cued extinction. Inhibition of E2 synthesis in the BLA impaired heroin-cue EMR in both sexes. Notably, E2s actions are mediated by different ER mechanisms, ERα in males but ERß in females. CONCLUSIONS: This study is the first to demonstrate a behavioral role for centrally-produced E2 in the BLA and that E2 also impacts EMR of reward-associated stimuli in both sexes.

Paraventricular Nucleus of the Hypothalamus Oxytocin and Incubation of Heroin Seeking.

INTRODUCTION: There are numerous pharmacologic treatments for opioid use disorder (OUD), but none that directly target the underlying addictive effects of opioids. Oxytocin, a peptide hormone produced in the paraventricular nucleus (PVN) of the hypothalamus, has been investigated as a potential therapeutic for OUD. Promising preclinical and clinical results have been reported, but the brain region(s) and mechanism(s) by which oxytocin impacts reward processes remain undetermined. METHODS: Here, we assess peripherally administered oxytocin's impacts on cued reinstatement of heroin seeking following forced abstinence and its effects on neuronal activation in the PVN and key projection regions. We also examine how designer receptors exclusively activated by designer drug (DREADD)-mediated activation or inhibition of oxytocinergic PVN neurons alters cued heroin seeking and social interaction. RESULTS: As predicted, peripheral oxytocin administration successfully decreased cued heroin seeking on days 1 and 30 of abstinence. Oxytocin administration also led to increased neuronal activity within the PVN and the central amygdala (CeA). Activation of oxytocinergic PVN neurons with an excitatory (Gq) DREADD did not impact cued reinstatement or social interaction. In contrast, suppression with an inhibitory (Gi) DREADD reduced heroin seeking on abstinence day 30 and decreased time spent interacting with a novel conspecific. DISCUSSION: These findings reinforce oxytocin's therapeutic potential for OUD, the basis for which may be driven in part by increased PVN-CeA circuit activity. Our results also suggest that oxytocin has distinct signaling and/or other mechanisms of action to produce these effects, as inhibition, but not activation, of oxytocinergic PVN neurons did not recapitulate the suppression in heroin seeking.

Older patients with primary central nervous system lymphoma: Survival and prognostication across 20 U.S. cancer centers.

There is a paucity of large-scale data delineating outcomes and prognostication of older patients with primary central nervous system lymphoma (PCNSL). We retrospectively analyzed 539 newly-diagnosed PCNSL patients ages ≥60 years across 20 U.S. academic centers. The median age was 70 years (range 60-88); at least one geriatric syndrome was present in 46%; the median Cumulative Index Ratings Scale-Geriatrics (CIRS-G) score was 6 (range, 0-27); and 36% had impairment in activities of daily living (ADL). The most common induction regimens were high-dose methotrexate (HD-MTX) ± rituximab; methotrexate, temozolomide, rituximab (MTR); and rituximab, methotrexate, procarbazine, vincristine (R-MPV). Overall, 70% of patients achieved remission, with 14% undergoing consolidative autologous stem cell transplant (ASCT) and 24% receiving maintenance. With 58-month median follow-up, median progression-free survival (PFS) and overall survival (OS) were 17 months (95% CI 13-22 months) and 43 months (95% CI 31-56 months), respectively. Three-year PFS and OS were highest with MTR (55% and 74%, respectively). With single-agent methotrexate ± rituximab, 3-year PFS and OS were 30% (p = .0002) and 47% (p = .0072). On multivariate analysis, increasing age at diagnosis and Cooperative Oncology Group (ECOG) performance status (PS) was associated with inferior PFS; age, hypoalbuminemia, higher CIRS-G score, and ECOG PS adversely affected OS. Among patients receiving maintenance, 3-year PFS was 65% versus 45% without maintenance (p = 0.02), with 3-year OS of 84% versus 61%, respectively (p = .0003). Altogether, outcomes in older PCNSL patients appeared optimized with HD-MTX combination induction regimens and maintenance therapy. Furthermore, several prognostic factors, including geriatric measures, were associated with inferior outcomes.

Matrix metalloproteinase activity during methamphetamine cued relapse.

Relapse to drug seeking involves transient synaptic remodelling that occurs in response to drug-associated cues. This remodelling includes activation of matrix metalloproteinases (MMPs) to initiate catalytic signalling in the extracellular matrix in the nucleus accumbens core (NAcore). We hypothesized that MMP activity would be increased in the NAcore during cue-induced methamphetamine (meth) seeking in a rat model of meth use and relapse. Male and female rats had indwelling jugular catheters and bilateral intracranial cannula targeting the NAcore surgically implanted. Following recovery, rats underwent meth or saline self-administration (6 h/day for 15 days) in which active lever responding was paired with a light + tone stimulus complex, followed by home cage abstinence. Testing occurred after 7 or 30 days of abstinence. On test day, rats were microinjected with a fluorescein isothiocyanate (FITC)-quenched gelatin substrate that fluoresces following cleavage by MMP-2,9, allowing for the quantification of gelatinase activity during cued-relapse testing. MMP-2,9 activity was significantly increased in the NAcore by meth cues presentation after 7 and 30 days of abstinence, indicating that remodelling by MMPs occurs during presentation of meth associated cues. Surprisingly, although cue-induced seeking increased between Days 7 and 30, MMP-2,9 activity did not increase. These findings indicate that although MMP activation is elicited during meth cue-induced seeking, MMP activation did not parallel the meth seeking that occurs during extended drug abstinence.

Negative pressure wound therapy on complex extremity wounds requiring coverage with a meshed bilayer wound matrix: a retrospective analysis.

OBJECTIVE: The treatment of complex extremity wounds is technically challenging. In this 5-year retrospective review, we compared the use of Integra Meshed Bilayer Wound Matrix (IMBWM; Integra LifeSciences, US) followed by a split-thickness skin graft (STSG) combined with negative pressure wound therapy (NPWT) versus IMBWM followed by STSG alone for the management of these wounds. METHOD: Data from patients undergoing management using IMBWM for a complex extremity wound coverage were collected. RESULTS: Among the 109 patients studied, the wounds of 62 patients were managed using IMBWM and NPWT, and 47 were managed using IMBWM alone. The most common aetiology of these injuries was trauma. Wound size and location were similar for each group, ranging in size from 2-30cm2 and being primarily on the forearm, followed by the leg and arm. There was a significantly greater take of the IMBWM+STSG with NPWT (96.8%) compared to without NPWT (85.1%, p=0.03). There were significantly fewer reapplications of the dermal matrix required in the NPWT group (3.2%) versus the non-NPWT group (14.9%, p=0.03). There were significantly fewer postoperative complications, prior to STSG, in the NPWT group (3.2%) versus the non-NPWT group (14.9%, p=0.03). CONCLUSION: The combination of IMBWM with NPWT leads to a higher success rate, and can reduce the number of dermal matrix reapplications and postoperative complications, in the setting of complex extremity wounds. The use of IMBWM in combination with NPWT has the potential to improve both surgical procedures and patient outcomes in this setting.

Publication Trends of Residents Accepted for Shoulder and Elbow Fellowships.

This study aims to evaluate the research productivity trends in orthopaedic residents who were selected for shoulder and elbow fellowships from 2010 to 2019. We hypothesize that residents matching into orthopaedic shoulder and elbow fellowships are increasing both their publication number and publication quality from 2010 to 2019. Fellows of orthopaedic shoulder and elbow programs from 2010 to 2019 were identified through publicly accessible information on fellowship programs. Each fellow's publication data during their residency was collected via publicly available search engines, and analyzed to include: fellowship year, residency years, fellowship program and location, total publications, number of publications in high-impact general orthopaedic and shoulder and elbow journals, and authorship position. A total of 176 orthopaedic shoulder and elbow fellows from 17 different programs were identified and included in the study. The fellows produced a total of 668 publications, published 172 articles in high impact journals, and had first authorship on 49% of the studies. On average, there were 3.8 publications per fellow per year from 2010 to 2019. There were 5.7 publications produced per fellow in 2018-2019, compared to just 2.92 publications per fellow in 2010-2011. Overall, there was an increasing trend in publications, publications in high impact journals, and first authorship publications per applicant matching into shoulder and elbow fellowship from 2010 to 2019. (Journal of Surgical Orthopaedic Advances 31(4):205-208, 2022).

Practice Patterns Among Hand Surgeons According to Primary Residency Training: A National Surgical Quality Improvement Project Study.

INTRODUCTION: Hand surgery fellowships accept applicants from 3 different residencies: general surgery, orthopedic surgery, and plastic surgery. Although all of these specialties culminate into a board-certified hand surgeon, each specialty receives drastically different training in residency, which can have effects on which procedures these surgeons feel comfortable performing in their own practices. This study aims to compare practice patterns and complication rates among hand surgeons by residency training. METHODS: The National Surgical Quality Improvement Program database was queried between the years of 2014 and 2018 for all Current Procedural Terminology codes pertaining to upper-extremity surgical procedures performed below the elbow. Procedures not performed by a general, orthopedic, or plastic surgeon were excluded, as well as polytraumas. Procedures were then stratified by anatomic region, tissue type, and primary specialty of the attending surgeon. Data collected included the number of each procedure, patient complexity, and complications. Statistical analysis consisted of a t test for continuous variables, χ2 analysis for categorical variables, and linear regression analysis to compare complications rates between specialties. RESULTS: A total of 76,980 unique cases were included in our analysis: 4979 (6.4%) at the elbow, 43,680 (56.7%) at the forearm/wrist, 23,284 (30.2%) at the hand, 1421 (1.8%) flaps/grafts, 285 (0.4%) vascular, and 3331 (4.3%) neurological. Orthopedics performed most (79.5%) of the procedures, whereas plastic surgeons and general surgeons performed 17.3% and 3.1%, respectively. There were also significant differences by anatomic location/type of procedure, with orthopedic surgeons performing 99.2% of procedures at the elbow but only 67.7% of procedures at the hand. Linear regression analysis showed general surgeons had the lowest complication rates. CONCLUSIONS: Our data show significant differences in the number of upper-extremity surgeries performed by surgeons from each specialty at different anatomic locations.This could be due to differences in training during residency or proportionately more orthopedic surgeons being "full-time" hand surgeons. These data could affect hiring patterns in hospitals seeking hand surgeons depending on the variety of pathology encountered at that particular institution.

Cost Analysis and National Trends in the Treatment of Dupuytren Contracture Comparing Collagenase Injection, Needle Fasciotomy, and Open Fasciectomy Procedures.

BACKGROUND: Dupuytren contracture (DC) is a common disorder characterized by progressive fibrosis of palmar fascia. This study analyzed cost trends of 3 common treatments for DC: fasciotomy, fasciectomy, and collagenase injection (CI)/cord manipulation. METHODS: The Vizient Clinical Data/Resource Manager electronic database was reviewed for all procedures for the treatment of DC at participating hospitals in the United States (US) from October 1, 2015, to September 1, 2019. Cases were placed into 1 of 3 categories: (1) CI, (2) needle fasciotomy (NF), and (3) open fasciectomy (OF). Total and direct costs were averaged for each procedure and compared nationally and regionally. Temporal trends and specific market share were analyzed. One-tailed t test and Pearson correlation analysis was performed (P < 0.05 and r > 0.9 or r < -0.9 was considered significant). RESULTS: A total of 22,974 total cases were identified. A total of 16,966 OF, 3962 NF, and 2046 CI were performed. There was a nearly a 4-fold increase in number of procedures to treat DC from 2015 to 2018. Market share percentage of each procedure stayed relatively similar over time. However, market share percentage differed between procedures. Needle fasciotomy had the lowest market share percentage approximately 7%. Collagenase injection had the highest average cost at US $4453.66 and was significantly higher than OF at US $3394.90 and NF at US $2010.75. Cost and distribution of procedures were further analyzed by geographic regions. In 2018, 32% of procedures performed were in the Northeastern US, 29% in the Midwestern US, 23% in the Southern US, and 16% in the Western US. Total number of Dupuytren procedures increased more than 300% in all regions across the US from 2015 to 2018. In every region, NF was the lowest cost intervention. Cost of OF and CI varied between regions and was often the most expensive intervention. CONCLUSIONS: Treatment of DCs with NF seems to be the least costly treatment option. Needle fasciotomy seems to be the least commonly performed procedure. Regional data show variations in the cost of OF and CI. However, OF has the majority market share nationally and regionally. Although the cost of these procedures seems to vary regionally, the type of procedures being performed seem to be similar across regions.

Current Treatment Options for Older Patients with Hodgkin Lymphoma.

OPINION STATEMENT: Older adults with Hodgkin lymphoma (HL), commonly defined as age ≥ 60 years, represent approximately 20% of the total HL population. Historically, they have significantly inferior outcomes compared with younger patients. The cause of this is multifactorial, including biologic differences (e.g., mixed cellularity and EBV-related disease); high incidence of advanced stage disease; and frequency of comorbidities and decreased organ reserve leading to poorer tolerability of therapy with increased toxicity, including treatment-related mortality. Pretreatment evaluation for older HL patients should entail a geriatric assessment (GA), with evaluation of functional status and comorbidities (e.g., geriatric cumulative illness rating scale, CIRS-G) to determine fitness. Furthermore, treatment selection should be based in part on GA, with fit older patients receiving curative chemotherapy-based regimens and unfit or frail patients considering less intensive or non-chemotherapy-based platforms. Additionally, there may be consideration for pre-phase of therapy (e.g., pulse steroids) in order to improve performance status. The inclusion of anthracycline therapy appears important, while bleomycin-containing regimens (e.g., ABVD) may be associated with prohibitive pulmonary toxicity, and intensive therapies such as BEACOPP are too toxic. benefit ratio/benefit ratio, a priori omission of bleomycin may also be considered (i.e., AVD), especially for patients older than 70 years of age. In addition, newer regimens for older HL patients integrating novel therapeutic agents into frontline treatment have emerged as effective and tolerable options. Data incorporating brentuximab vedotin sequentially before and after AVD chemotherapy represent the best-reported outcomes in older HL patients to date. In the relapsed/refractory setting, salvage chemotherapy regimens followed by autologous stem cell transplantation should be considered for fit patients, while less intensive treatment, including the use of novel targeted agents, is an option for unfit or frail patients. In this review, we examine the epidemiology, importance of GA, and current treatment options for older HL patients.

Ca2+-mediated activation of the skeletal-muscle ryanodine receptor ion channel.

Cryo-electron micrograph studies recently have identified a Ca2+-binding site in the 2,200-kDa ryanodine receptor ion channel (RyR1) in skeletal muscle. To clarify the role of this site in regulating RyR1 activity, here we applied mutational, electrophysiological, and computational methods. Three amino acid residues that interact directly with Ca2+ were replaced, and these RyR1 variants were expressed in HEK293 cells. Single-site RyR1-E3893Q, -E3893V, -E3967Q, -E3967V, and -T5001A variants and double-site RyR1-E3893Q/E3967Q and -E3893V/E3967V variants displayed cellular Ca2+ release in response to caffeine, which indicated that they retained functionality as caffeine-sensitive, Ca2+-conducting channels in the HEK293 cell system. Using [3H]ryanodine binding and single-channel measurements of membrane isolates, we found that single- and double-site RyR1-E3893 and -E3967 variants are not activated by Ca2+ We also noted that RyR1-E3893Q/E3967Q and -E3893V/E3967V variants maintain caffeine- and ATP-induced activation and that RyR1-E3893Q/E3967Q is inhibited by Mg2+ and elevated Ca2+ RyR1-T5001A exhibited decreased Ca2+ sensitivity compared with WT-RyR1 in single-channel measurements. Computational methods suggested that electrostatic interactions between Ca2+ and negatively charged glutamate residues have a critical role in transducing the functional effects of Ca2+ on RyR1. We conclude that the removal of negative charges in the recently identified RyR1 Ca2+-binding site impairs RyR1 activation by physiological Ca2+ concentrations and results in loss of binding to Ca2+ or reduced Ca2+ affinity of the binding site.

Sex differences in behavior, cognitive, and physiological recovery following methamphetamine administration.

Intact executive functions are required for proper performance of cognitive tasks and relies on balance of excitatory and inhibitory (E/I) transmission in the medial prefrontal cortex (mPFC). Hypofrontality is a state of decreased activity in the mPFC and is seen in several neuropsychiatric conditions, including substance use disorders. People who chronically use methamphetamine (meth) develop hypofrontality and concurrent changes in cognitive processing across several domains. Despite the fact that there are sex difference in substance use disorders, few studies have considered sex as a biological variable regarding meth-mediated hypoactivity in mPFC and concurrent cognitive deficits. Hypofrontality along with changes in cognition are emulated in rodent models following repeated meth administration. Here, we used a meth sensitization regimen to study sex differences in a Temporal Order Memory (TOM) task following short (7 days) or prolonged (28 days) periods of abstinence. GABAergic transmission, GABAA receptor (GABAAR) and GABA Transporter (GAT) mRNA expression in the mPFC were evaluated with patch-clamp recordings and RT-qPCR, respectively. Both sexes sensitized to the locomotor activating effects of meth, with the effect persisting in females. After short abstinence, males and females had impaired TOM and increased GABAergic transmission. Female rats recovered from these changes after prolonged abstinence, whereas male rats showed enduring changes. In general, meth appears to elicit an overall decrease in GABAAR expression after short abstinence; whereas GABA transporters are decreased in meth female rats after prolonged abstinence. These results show sex differences in the long-term effects of repeated meth exposure and suggest that females have neuroprotective mechanisms that alleviate some of the meth-mediated cognitive deficits.

Estrogen receptor beta signaling enhances extinction memory recall for heroin-conditioned cues in a sex- and region-specific manner.

Return to use, or relapse, is a major challenge in the treatment of opioid use disorder (OUD). Relapse can be precipitated by several factors, including exposure to drug-conditioned cues. Identifying successful treatments to mitigate cue-induced relapse has been challenging, perhaps due to extinction memory recall (EMR) deficits. Previously, inhibition of estradiol (E2) signaling in the basolateral amygdala (BLA) impaired heroin-cue EMR. This effect was recapitulated by antagonism of BLA estrogen receptors (ER) in a sex-specific manner such that blocking ERα in males, but ERß in females, impaired EMR. However, it is unclear whether increased E2 signaling, in the BLA or systemically, enhances heroin-cue EMR. We hypothesized that ERß agonism would enhance heroin-cue EMR in a sex- and region-specific manner. To determine the capacity of E2 signaling to improve EMR, we pharmacologically manipulated ERß across several translationally designed experiments. First, male and female rats acquired heroin or sucrose self-administration. Next, during a cued extinction session, we administered diarylpropionitrile (DPN, an ERß agonist) and tested anxiety-like behavior on an open field. Subsequently, we assessed EMR in a cue-induced reinstatement test and, finally, measured ERß expression in several brain regions. Across all experiments, females took more heroin and sucrose than males and had greater responses during heroin-cued extinction. Administration of DPN in the BLA enhanced EMR in females only, driven by ERß's impacts on memory consolidation. Interestingly, however, systemic DPN administration improved EMR for heroin cues in both sexes across several different tests, but did not impact sucrose-cue EMR. Immunohistochemical analysis of ERß expression across several different brain regions showed that females only had greater expression of ERß in the basal nucleus of the BLA. Here, in several preclinical experiments, we demonstrated that ERß agonism enhances heroin-cue EMR and has potential utility in combatting cue-induced relapse.

Prevalence and Prognostication of CD5+ Mature T-Cell Lymphomas.

Background: T-cell lymphomas (TCLs) are a group of heterogenous cancers with poor rates and duration of response. There remains a great challenge in risk stratification of these cancers. Cluster of differentiation (CD) 5 has shown prognostic implication in many subtypes of B-cell lymphoma; however, its role in TCLs is not known. Methods: We performed a single-institution retrospective analysis of newly diagnosed patients with TCL. CD5 positivity was determined based on positive results via immunohistochemistry and/or flow cytometry. We used univariate and multivariable analysis of biological factors to assess their association with survival outcomes. Results: A total of 194 patients with TCL spanning 14 subtypes were identified. CD5 positivity was noted in 63% of patients, with the highest proportion of CD5 expression in TFH TCL (93.9%), PTCL-NOS (82.9%), and ATLL (77.8%) (p = 0.00004). Older age at diagnosis (p = 0.001), stage III or IV disease (p = 0.05), and bone marrow involvement (p = 0.003) were also associated with CD5 expression. Complete response rates were numerically lower in patients with CD5+ TCL across all subtypes. OS/PFS was not statistically associated with CD5 status in the overall cohort; however there was significantly decreased OS in CD5+ TFH TCL (p = 0.04) and CD5+ ATLL (p = 0.04) patients. Conclusions: This study represents the first to examine CD5 expression as a prognostic biomarker for outcomes in TCL. The frequent expression of CD5 in the most common nodal TCL in the Western world underpins its potential as an attractive target for cellular therapies. Confirmation of these findings in a larger cohort and investigation of potential pathophysiological mechanisms explaining our observations are planned.

Efficacy and safety of bendamustine for lymphodepletion before lisocabtagene maraleucel.

Bendamustine has been retrospectively shown to be an effective and safe lymphodepletion regimen prior to the anti-CD19 chimeric antigen receptor T cell (CART) products tisagenlecleucel and axicabtagene ciloleucel, as well as the anti-BCMA CART products idecabtagene vicleucel and ciltacabtagene autoleucel. However, bendamustine as lymphodepletion prior to lisocabtagene maraleucel (liso-cel), a 4-1BB co-stimulated, fixed CD4:CD8 ratio anti-CD19 CART product, has not been described yet. Thus, we studied a cohort of sequentially-treated patients with large B-cell lymphomas who received bendamustine lymphodepletion before liso-cel at the University of Pennsylvania between 5/2021 and 12/2023 (n = 31). Patients were evaluated for toxicities and responses. Of note, 7 patients (22.6%) would have dnot met the inclusion criteria for the registrational liso-cel clinical trials, mostly due to older age. Overall and complete response rates were 76.9% and 73.1%, respectively. At a median follow-up of 6.3 months, the 6-month progression-free and overall survival were 59.9% and 91.1%, respectively. Rates of cytokine-release syndrome (CRS) and neurotoxicity (ICANS) of any grade were 9.7% and 9.7%, respectively, with no grade ≥ 3 events. No infections were reported during the first 30 days following liso-cel infusion. Neutropenia ≥ grade 3 was observed in 29.0% of patients; thrombocytopenia ≥ grade 3 occurred in 9.7%. In conclusion, bendamustine lymphodepletion before liso-cel appears to be a strategy that can drive tumor responses while ensuring a mild toxicity profile.

Bendamustine lymphodepletion before axicabtagene ciloleucel is safe and associates with reduced inflammatory cytokines.

ABSTRACT: Lymphodepletion (LD) is an integral component of chimeric antigen receptor T-cell (CART) immunotherapies. In this study, we compared the safety and efficacy of bendamustine (Benda) to standard fludarabine/cyclophosphamide (Flu/Cy) LD before CD19-directed, CD28-costimulated CART axicabtagene ciloleucel (axi-cel) for patients with large B-cell lymphoma (LBCL) and follicular lymphoma (FL). We analyzed 59 patients diagnosed with LBCL (n = 48) and FL (n = 11) consecutively treated with axi-cel at the University of Pennsylvania. We also analyzed serum samples for cytokine levels and metabolomic changes before and after LD. Flu/Cy and Benda demonstrated similar efficacy, with complete remission rates of 51.4% and 50.0% (P = .981), respectively, and similar progression-free and overall survivals. Any-grade cytokine-release syndrome occurred in 91.9% of patients receiving Flu/Cy vs 72.7% of patients receiving Benda (P = .048); any-grade neurotoxicity after Flu/Cy occurred in 45.9% of patients and after Benda in 18.2% of patients (P = .031). In addition, Flu/Cy was associated with a higher incidence of grade ≥3 neutropenia (100% vs 54.5%; P < .001), infections (78.4% vs 27.3%; P < .001), and neutropenic fever (78.4% vs 13.6%; P < .001). These results were confirmed both in patients with LBCL and those with FL. Mechanistically, patients with Flu/Cy had a greater increase in inflammatory cytokines associated with neurotoxicity and reduced levels of metabolites critical for redox balance and biosynthesis. This study suggests that Benda LD may be a safe alternative to Flu/Cy for CD28-based CART CD19-directed immunotherapy with similar efficacy and reduced toxicities. Benda is associated with reduced levels of inflammatory cytokines and increased anabolic metabolites.

Primary Repair of Upper Extremity Peripheral Nerve Injuries: An NSQIP Analysis From 2010 to 2016.

BACKGROUND: To identify the rate of 30-day complications after primary repair of upper extremity peripheral nerve injuries, associated diagnoses, and postoperative complication rate. METHODS: The American College of Surgeons National Surgical Quality Improvement Program database was reviewed from 2010 to 2016. Current Procedural Terminology codes consistent with primary nerve repair of the upper extremity were identified and included in the analysis. Patient demographics, comorbidities, type of procedure (elective/emergent), wound class, operative time, and 30-day complications were recorded. Patients with isolated upper extremity nerve injuries (isolated) were compared with those with peripheral nerve injuries in addition to bone, tendon, or soft tissue injuries (multiple). RESULTS: In all, 785 patients were identified as having upper extremity nerve repairs (0.16%). Of them, 64% were men and 36% were women; the average patient age was 40 years. The most common indication for surgery was injury to the digits (54% of cases). Thirty-day adverse events occurred in 3% of all cases. Isolated nerve injury occurred in 43% of patients, whereas 57% had additional injuries. The multiple injury group had a significantly higher complication rate compared with the isolated group (1% vs 4.5%) (P = .007). Repair of tendon at forearm or wrist was the most common concurrent procedure performed. CONCLUSIONS: Thirty-day complications among upper extremity peripheral nerve injuries are low, accounting for 3% of cases. Return to the operating room accounted for nearly half of all complications. Patients in the multiple injury group accounted for more than half of these and had a significantly higher complication rate compared with patients with isolated nerve injuries.

Primary Repair versus Reverse End-to-Side Coaptation by Anterior Interosseous Nerve Transfer in Proximal Ulnar Nerve Injuries.

BACKGROUND: Proximal ulnar nerve lacerations are challenging to treat because of the complex integration of sensory and motor function in the hand. The purpose of this study was to compare primary repair and primary repair plus anterior interosseous nerve (AIN) reverse end-to-side (RETS) coaptation in the setting of proximal ulnar nerve injuries. METHODS: A prospective cohort study was performed of all patients at a single, academic, level I trauma center from 2014 to 2018 presenting with isolated complete ulnar nerve lacerations. Patients underwent either primary repair (PR) only or primary repair and AIN RETS (PR + RETS). Data collected included demographic information; quick Disabilities of the Arm, Shoulder and Hand questionnaire score; Medical Research Council score; grip and pinch strength; and visual analogue scale pain scores at 6 and 12 months postoperatively. RESULTS: Sixty patients were included in the study: 28 in the PR group and 32 in the RETS + PR group. There was no difference in demographic variables or location of injury between the two groups. Average quick Disabilities of the Arm, Shoulder and Hand questionnaire scores for the PR and PR + RETS groups were 65 ± 6 and 36 ± 4 at 6 months and 46 ± 4 and 24 ± 3 at 12 months postoperatively, respectively, and were significantly lower in the PR + RETS group at both points. Average grip and pinch strength were significantly greater for the PR + RETS group at 6 and 12 months. CONCLUSION: This study demonstrated that primary repair of proximal ulnar nerve injuries plus AIN RETS coaptation yielded superior strength and improved upper extremity function when compared with PR alone. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, II.

Social solidarity, social infrastructure, and community food access.

This study examines the case of community resource mobilization within the context of a farmers market incentive program in Washington D.C., USA to illustrate the ways in which providing opportunities for people impacted by food inequities to develop and lead programming can help to promote food access. Through an analysis of interviews with 36 participants in the Produce Plus program, some of whom also served as paid staff and volunteers with the program, this study examines the ways that group-level social interactions among program participants helped to ensure the program was accessible and accountable to the primarily Black communities that it serves. Specifically, we explore a particular set of social interactions, which we collectively term social solidarity, as a community-level form of social infrastructure that program volunteers and participants mobilized to support access to fresh, local food in their communities. We also examine the elements of the Produce Plus program that contributed to the flow of social solidarity within the program, providing insight into the ways in which the structure of food access programs can serve as a social conduit to facilitate or hinder the mobilization of community cultural resources like social solidarity.

Perirhinal to prefrontal circuit in methamphetamine induced recognition memory deficits.

Return to methamphetamine (meth) use is part of an overarching addictive disorder hallmarked by cognitive sequela and cortical dysfunction in individuals who use meth chronically. In rats, long access meth self-administration produces object recognition memory deficits due to drug-induced plasticity within the perirhinal cortex (PRH). PRH projections are numerous and include the medial prefrontal cortex (mPFC). To evaluate the role of the PRH-mPFC reciprocal circuit in novel object recognition memory, a rgAAV encoding GFP-tagged Cre recombinase was infused into the PRH or the mPFC and rats were tested for recognition memory. On test day, one group explored both familiar and novel objects. A second group explored only familiar objects. GFP and Fos expression were visualized in the mPFC or PRH. During exploration, PRH neurons receiving input from the mPFC were equally activated by exploration of novel and familiar objects. In contrast, PRH neurons that provide input to the mPFC were disproportionately activated by novel objects. Further, the percent of Fos + cells in the PRH positively correlated with recognition memory. As such, the flow of communication appears to be from the PRH to the mPFC. In agreement with this proposed directionality, chemogenetic inhibition of the PRH-mPFC circuit impaired object recognition memory, whereas chemogenetic activation in animals with a history of long access meth self-administration reversed the meth-induced recognition memory deficit. This finding informs future work aimed at understanding the role of the PRH, mPFC, and their connectivity in meth associated memory deficits. These data suggest a more complex circuitry governing recognition memory than previously indicated with anatomical or lesion studies.